110. A Phase 3, Multicenter, Double-blind, Randomized Clinical Trial to Evaluate the Efficacy and Safety of Ceftolozane/Tazobactam Plus Metronidazole Versus Meropenem in Chinese Participants With Complicated Intra-abdominal Infections

Abstract Background In China, the prevalence of infections due to multidrug-resistant gram-negative bacteria is high and additional treatment options for complicated intra-abdominal infections (cIAI) are needed. This study compared the efficacy and safety of ceftolozane/tazobactam (C/T) + metronidazole (MTZ) versus meropenem (MEM) + placebo (pbo) for the treatment of cIAI in adult Chinese participants. Methods This was a phase 3, double-blind study conducted at 21 centers in China (NCT03830333). Participants aged 18-75 years with cIAI requiring surgical intervention within 24 hours of study drug administration were stratified by site of infection and randomized 1:1 to receive 1.5 g C/T (1 g ceftolozane and 0.5 g tazobactam) + 0.5 g MTZ administered intravenously (IV) every 8 hours (q8h) or 1 g MEM + pbo administered IV q8h for 4-14 days. The primary endpoint was clinical cure at test of cure (TOC) in the clinically evaluable (CE) population. Secondary endpoints included rates of clinical cure, per-participant microbiologic response, per-pathogen microbiologic response, and adverse events (AE). Non-inferiority for clinical cure at TOC in the CE population was confirmed if the lower bound of the 2-sided 95% CI for the between-treatment difference in the clinical cure rate was larger than −12.5%. Results A total of 134 participants were randomized to each treatment group. Demographics and baseline characteristics were generally well balanced between treatment groups (Table 1). The median (range) age in the ITT population was 50 (18-75) years and 61% were men. The most frequent sites of infection were the appendix (C/T + MTZ, 50.0%; MEM + pbo, 49.3%) and gallbladder (C/T + MTZ, 27.6%; MEM + pbo, 29.1%). Overall, the most frequently isolated pathogens were Escherichia coli (61.4%) and Klebsiella pneumoniae (17.3%); few anaerobes were isolated (Table 1). C/T + MTZ was non-inferior to MEM + pbo for clinical cure in the CE population (C/T + MTZ, 95.2%; MEM + pbo, 93.1%; difference, 2.1% [95% CI, −4.7% to 8.8%]). Results for key secondary endpoints were comparable between treatment groups (Table 2). Rates of AEs were generally similar between treatment groups (Table 3). Conclusion C/T + MTZ was non-inferior to MEM + pbo in the treatment of adult Chinese participants with cIAI and demonstrated a favorable safety profile. Disclosures Xiaofei Chen, n/a, MSD, China (Employee) Xiaoling Du, n/a, MSD, China (Employee) Ye Wang, n/a, MSD, China (Employee) Hui Wang, n/a, MSD, China (Employee) Fang Sun, n/a, MSD, China (Employee) Matthew G. Johnson, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Mekki Bensaci, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Jennifer A. Huntington, PharmD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Christopher Bruno, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee)

Background. Diabetic foot osteomyelitis (DFO) remains a significant comorbidity in diabetes and often requires both surgical and medical interventions. Surgical bone resection with proximal margins is performed for treatment at our institution to guide antimicrobial therapy. Optimal antibiotic duration often remains unclear, along with clinical outcomes with negative margins. We evaluate if negative bone margins predict outcomes of DFO at one year in our county hospital.
Methods. A retrospectively cohort study assessed adult patients undergoing DFO amputations between 9/2016 to 9/2019. Patient data collected included demographics, smoking history, hemoglobin A1c (HbA1c), basic labs, microbiology, antibiotic duration, bone margin pathology. Physician review of records determined if intervention was successful. Primary outcome was met if no further amputation at the same site was required in the following 12 months.
Results. Of 92 patients, 57 had negative margins and 35 had positive margins for pathology confirmed osteomyelitis. Smoking history was significant in positive margins (35.1% vs 57.1%; p=0.038). Patients with negative margins had a successful outcome at 12 months compared to positive margins (86% vs 66%; p=0.003), but no significant differences in outcome at 6 months. Antibiotic days was reduced in negative margin individuals (mean 18 vs 30 days; p=0.001). Negative margins also demonstrated significant lower rates of readmission at 12 months (p=0.015). Staphylococcus aureus was notable in positive vs negative margins (57.1% vs 29.8%; p=0.017). MSSA was significantly noted in positive margins (45.7% vs 14%; p=0.001). MRSA was similar regardless of margin results (15.8% vs 11.4%; p=0.399). Initial ESR, CRP and HbA1c were similar between groups.
Conclusion. Our study noted that negative proximal bone margins resulted in more successful outcomes at 12 months and less days of antimicrobial therapy. Patients with negative margins had lower rates of readmission at 12 months for surgical site complications. Negative proximal bone margins results can guide antibiotic therapy and improve outcomes of resections. Presence of S. aureus was significant in positive margins and likely warrant consideration for further aggressive intervention.

Clinical Characteristics of Patients with Diabetic Foot Osteomyelitis
Clinical demographics, antibiotic usage, microbiology and results of patients presenting for diabetic foot osteomyelitis needing surgical amputation intervention. Abbreviations: HbA1c -Hemoglobin A1c; MSSA -methicillin-susceptible Staphylococcus aureus; MRSA -methicillin-resistant Staphylococcus aureus; CRP -C-reactive protein; ESR -erythrocyte sedimentation rate Disclosures. All Authors: No reported disclosures

A Phase 3, Multicenter, Double-blind, Randomized Clinical Trial to Evaluate the Efficacy and Safety of Ceftolozane/Tazobactam Plus Metronidazole Versus Meropenem in Chinese Participants With Complicated Intra-abdominal Infections
Yihong Sun, MD, PhD, FRCS 1 ; Jia Fan, MD, PhD, FACS 1 ; Gang Chen, n/a 2 ; Xiaofei Chen, n/a 3 ; Xiaoling Du, n/a 3 ; Ye Wang, n/a 3 ; Hui Wang, n/a 3 ; Fang Sun, n/a 3 ; Matthew G. Background. In China, the prevalence of infections due to multidrug-resistant gram-negative bacteria is high and additional treatment options for complicated intra-abdominal infections (cIAI) are needed. This study compared the efficacy and safety of ceftolozane/tazobactam (C/T) + metronidazole (MTZ) versus meropenem (MEM) + placebo (pbo) for the treatment of cIAI in adult Chinese participants.
Methods. This was a phase 3, double-blind study conducted at 21 centers in China (NCT03830333). Participants aged 18-75 years with cIAI requiring surgical intervention within 24 hours of study drug administration were stratified by site of infection and randomized 1:1 to receive 1.5 g C/T (1 g ceftolozane and 0.5 g tazobactam) + 0.5 g MTZ administered intravenously (IV) every 8 hours (q8h) or 1 g MEM + pbo administered IV q8h for 4-14 days. The primary endpoint was clinical cure at test of cure (TOC) in the clinically evaluable (CE) population. Secondary endpoints included rates of clinical cure, per-participant microbiologic response, per-pathogen microbiologic response, and adverse events (AE). Non-inferiority for clinical cure at TOC in the CE population was confirmed if the lower bound of the 2-sided 95% CI for the between-treatment difference in the clinical cure rate was larger than −12.5%.

Session: O-23. New Developments in Antibiotic Efficacy
Background. Debridement, antibiotics, and implant retention (DAIR) is appropriate for select acute postoperative and hematogenous periprosthetic joint infections (PJIs). However, the optimal duration of antimicrobial therapy in patients treated with DAIR has not been defined. Therefore, we aimed to identify the ideal duration of parenteral and oral antibiotics after DAIR.
Methods. We performed a retrospective study of patients >18 years of age with hip or knee PJI managed with DAIR between January 1, 2008, and December 31, 2018, at Mayo Clinic. PJI was defined using criteria adapted from the International Consensus Meeting on PJI. The outcome was defined as either PJI recurrence or unplanned reoperation due to infection. Joint-stratified Cox proportional hazards regression models with time-dependent covariates were used to assess nonlinear effects of antibiotic duration. Hazard ratios were computed based on prespecified time points for comparison, whereas p-values represented the overall effect across the entire range of durations.
Results. There were 247 unique episodes of PJI in 237 patients during the study period. Parenteral antibiotics were given in 99.2% of cases (n=245). This was followed by chronic oral antibiotic suppression in 92.2% (n=226) with a median duration of 2.2 years (1.0-4.1).
DAIR failed in 65 cases over a median follow-up of 4.4 years, with a 5-year cumulative incidence of 28.1%. After adjustment for risk factors, there was no significant association between duration of parenteral antibiotics and treatment failure (p=0.203), with no difference between four versus six weeks (HR 1.11; 95% CI 0.71-1.75) ( Figure  1). However, both use and longer duration of oral antibiotic therapy was associated with a lower risk of failure (p=0.006). To account for the possibility that this association was driven by results during early follow-up, conditional analyses at one-and two-year follow-up were performed. Both showed a significantly lower risk for a longer duration of antibiotics (Figure 2).